Immunotherapies, including biologics and cell-based therapies, are emerging as highly promising and effective strategies for the treatment of cancer. Accompanying the great potential of these approaches are continuing challenges, including 1) untargeted global immune modulation associated with biologics, resulting in serious side effects; 2) challenges in scalability of cell-based therapies (e.g., adoptive/CAR-T therapies) and bispecifics, 3) lack of differentiation, as most efforts are focused on relatively few therapeutic targets and mechanisms; and 4) the lack of flexible platforms to rapidly and efficiently target new indications and mechanisms. To address these challenges, we describe a novel class of soluble precision biologics for the treatment of cancer. Our approach manipulates antigen-specific (i.e., clonal) lymphocyte populations by covalently linking single chain peptide-MHC (sc-pMHC) and costimulatory molecules in a manner that recapitulates the proximity, orientation and overall organization experienced at the immunological synapse. The sc-pMHC unit serves to selectively target distinct T cell clones for the delivery of a modulatory domain that can represent any potential costimulatory function. These constructs are generated as Fc-fusion proteins (i.e., IgG) for enhanced avidity and stability. This combined targeting:modulation construct is referred to as synTac (artificial immunological Synapse for T-cell Activation). Using this strategy we have already demonstrated clonal-specific T cell proliferation and activation in vitro, and clonal T cell expansion in vivo. The extreme specificity associated with these reagents eliminates the extensive side effects associated with currently used immunotherapeutics and the highly modular design supports a wide range of indications and therapeutic mechanisms via substitution of the disease relevant peptide epitope and comodulatory modules, respectively. The proposed work focuses on the continued development of the synTac platform for the selective in vivo expansion of CTLs that specifically target malignancies. Our Specific Aims are: AIM 1: Continued development of the synTac fusion protein platform, including the exploration of new presentation platforms with altered stoichiometries and new comodualory domains. AIM 2: Assessment of affinity and overall molecular organization on synTac efficacy to realize new insights into cell surface receptor signaling and new strategies for controlling synTac therapeutic activity. AIM 3: Application of synTacs to specific disease regression models to investigate synTac function in melanoma and pancreatic cancer, using disease and tumor regression models, including HLA-A2 transgenics. The continued success of this program promises to deliver a unique and highly flexible platform for the rapid development, evaluation and implementation of a novel family of biologics to treat a range of indications via a number of distinct mechanisms, and position us to initiate clinical trials for pancreatic ductal adenocarcinoma.